Composition containing medicine extremely slightly soluble in water being excellent in eluting property and method for preparation thereof

ABSTRACT

A composition containing an extremely poorly water-soluble drug and obtained by treating, with a supercritical fluid or subcritical fluid of carbon dioxide, a mixture comprising a porous silica material and the extremely poorly water-soluble drug; and its production process. The porous silica material has an average pore diameter in a range of from 1 to 20 nm, pores having diameters within ±40% of the average pore size account for at least 60% of a total pore volume of the porous silica material, and in X-ray diffractometry, the porous silica material has at least one peak at a position of diffraction angle (2θ) corresponding to a d value of at least 1 nm. 
     The composition according to the present invention, which contains the extremely poorly water-soluble drug, is excellent in the dissolution of the extremely poorly water-soluble drug.

TECHNICAL FIELD

This invention relates to compositions containing an extremely poorlywater-soluble drug and permitting excellent dissolution, and also to aproduction process thereof.

BACKGROUND ART

2-Benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneis known to have excellent interleukin-1β production inhibiting effectand to be useful as preventives and therapeutics for immune systemdiseases, inflammatory diseases, ischemic diseases and the like(JP-A-12-198776). However, this compound is a drug having extremely lowsolubility in water and is poor in its dissolution from preparations.There is, accordingly, an outstanding demand for an improvement in itsdissolution.

As methods for improving the dissolution of extremely poorlywater-soluble drugs, techniques such as the micronization of the drugsand the preparation of derivatives of the drugs are known. Concerningextremely poorly water-soluble drugs such as2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,however, micronization cannot improve their dissolution, and theirconversion into derivatives leads to changes in drug activities andtherefore, is not preferred.

Also proposed as methods for making improvements in dissolution includea method which comprises treating a physiologically active substancesuch as nifedipine with carbon dioxide, which is in a supercriticalstate or subcritical state, or with liquid carbon dioxide (for example,JP-A-2002-302435). These methods can improve the dissolution of slightlywater-soluble drugs such as nifedipine, but cannot improve thedissolution of extremely poorly water-soluble drugs such as2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one.

DISCLOSURE OF THE INVENTION

An object of the present invention is, therefore, to provide acomposition containing an extremely poorly water-soluble drug andpermitting excellent dissolution and also its production process.

With the foregoing in view, the present inventors have proceeded with anextensive investigation. As a result, it has been found that acomposition excellent in the dissolution of a extremely poorlywater-soluble drug can be obtained when a mixture comprising a poroussilica material and the extremely poorly water-soluble drug is treatedwith a supercritical fluid or subcritical fluid of carbon dioxide,provided that the porous silica material has an average pore diameter ina range of from 1 to 20 nm, pores having diameters within ±40% of theaverage pore size account for at least 60% of a total pore volume of theporous silica material, and in X-ray diffractometry, the porous silicamaterial has at least one peak at a position of diffraction angle (2θ)corresponding to a d value of at least 1 nm. The above finding has ledto the completion of the present invention.

Described specifically, the present invention provides a compositioncontaining an extremely poorly water-soluble drug and obtained bytreating, with a supercritical fluid or subcritical fluid of carbondioxide, a mixture comprising a porous silica material and the extremelypoorly water-soluble drug, characterized in that the porous silicamaterial has an average pore diameter in a range of from 1 to 20 nm,pores having diameters within ±40% of the average pore size account forat least 60% of a total pore volume of the porous silica material, andin X-ray diffractometry, the porous silica material has at least onepeak at a position of diffraction angle (2θ) corresponding to a d valueof at least 1 nm; and also a process for the production of thecomposition.

By the present invention, a composition, which contains an extremelypoorly water-soluble drug and permits excellent dissolution, and itsproduction process can be provided.

BEST MODES FOR CARRYING OUT THE INVENTION

The extremely poorly water-soluble drug for use in the present inventioncan have a solubility of lower than 10 μg/mL, preferably lower than 5μg/mL, particularly preferably not higher than 1 μg/mL in water at 25°C.

No particular limitation is imposed on the kind of the extremely poorlywater-soluble drug for use in the present invention. Examples includeantipyretics, anti-inflammatories, analgesics, ataractics, sedatives,antitumor agents, antimicrobials, antibiotics, antilipemics,antitussives/expectorants, muscle relaxants, antiepileptics, antiulcers,antidepressants, antiallergics, cardiotonics, antiarrhythmics,vasodilators, hypotensors/diuretics, diabetes therapeutics,tuberculostatics, antirheumatics, steroids, narcotic antagonists,hormones, fat-soluble vitamins, anticoagulants, ischemic diseasetherapeutics, immune disease therapeutics, Alzheimer's diseasetherapeutics, osteoporosis therapeutics, angiopoiesis therapeutics,retinosis therapeutics, retinal vein occlusion therapeutics, seniledisciform macular degeneration, cerebrovascular spasm therapeutics,cerebral thrombosis therapeutics, cerebral infarction therapeutics,cerebral occlusion therapeutics, intracerebral hemorrhage therapeutics,subarachnoid hemorrhage therapeutics, hypertensive encephalopathytherapeutics, transient cerebral ischemic attack therapeutics,multi-infarct dementia therapeutics, arterial sclerosis therapeutics,Huntington's disease therapeutics, brain tissue disorder therapeutics,optic neuropathy therapeutics, glaucoma therapeutics, ocularhypertension therapeutics, retinal detachment therapeutics, arthritistherapeutics, antisepsis drugs, antiseptic shock drugs, antiasthmadrugs, pollakiuria/incontinentia therapeutics, atopic rhinitistherapeutics, allergic rhinitis therapeutics, cosmetic compositions,agrichemical compositions, insecticides, bactericides, herbicides,beverage or food compositions, and animal drug compositions.

Preferred specific examples of the extremely poorly water-soluble druginclude antirheumatics such as2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one(may hereinafter be referred to as “Compound A”; solubility in water at25° C.: 0.01 μg/mL), steroids such as prednisolone valerate acetate(solubility in water at 25° C.: 4.0 μg/mL), cholesterol (solubility inwater at 25° C.: 0.1 μg/mL), estradiol (solubility in water at 25° C.:3.6 μg/mL) and progesterone (solubility in water at 25° C.: 8.8 μg/mL),antiasthma drugs such as pranlukast (solubility in water at 25° C.: 0.9μg/mL), and allergic rhinitis therapeutics such as pranlukast(solubility in water at 25° C.: 0.9 μg/mL). Compound A is particularlypreferred.

The porous silica material for use in the present invention is a poroussilica material (may hereinafter be referred to as “the instant poroussilica material”) which is characterized in that the porous silicamaterial has an average pore diameter in a range of from 1 to 20 nm,pores having diameters within ±40% of the average pore size account forat least 60% of a total pore volume of the porous silica material, andin X-ray diffractometry, the porous silica material has at least onepeak at a position of diffraction angle (2θ) corresponding to a d valueof at least 1 nm.

The average pore diameter of the instant porous silica material can bedetermined by the gas adsorption method. Its measurement can beconducted, for example, by an automated specific surface area/poredistribution analyzer, “TRISTAR 3000” (manufactured by MicrometricsInstrument Corporation), or the like.

On the other hand, the expression that “in X-ray diffractometry of theinstant porous silica material, it has at least one peak at a positionof diffraction angle (2θ) corresponding to a d value of at least 1 nm”means that periodic structures of the d value corresponding to the peakangle exist in the porous silica material. This reflects a structure inwhich pores are arranged orderly at intervals of at least 1 nm. Theinstant porous silica material is, therefore, a porous silica materialin which pore diameters are sufficiently uniform.

It is to be noted that X-ray diffractometry can be performed, forexample, by an automated X-ray diffractometer system, “MXP 3”(manufactured by Mac Science Corporation), or the like.

The porous silica material for use in the present invention can have acomposition consisting of pure silica. As an alternative, it can be amixture of silica with one or more of aluminum (Al), titanium (Ti),magnesium (Mg), zirconium (Zr), gallium (Ga), beryllium (Be), yttrium(Y), lanthanum (La), tin (Sn), lead (Pb), vanadium (V), boron (B) andthe like.

Examples of the porous silica material for use in the present inventioninclude porous silica materials each having a skeleton of a polymerizedmetal oxide, typically porous silica materials each having a silicateskeleton. In the instant porous silica material, such metal-oxygen bondsare formed in a network structure, and as a whole, make up a porousmaterial. Also included as examples are porous silica materials each ofwhich has a skeleton containing, in place of a fraction of the siliconatoms in the silicate skeleton, other metal atoms such as aluminum,zirconium, tantalum, niobium, tin, hafnium, magnesium, molybdenum,cobalt, nickel, gallium, beryllium, yttrium, lanthanum, lead and/orvanadium atoms. Also usable are porous silica materials each of whichhas a skeleton containing such other metal atoms or silicon atoms in asilicate skeleton or a skeleton containing bonds of such other metalatoms and oxygen atoms.

It is to be noted that various metal atoms, organic functional groupsand/or inorganic functional groups may be added to or as side chainsbonded to atoms making up such a basic skeleton. Those containing, forexample, thiol groups, carboxyl groups, lower alkyl groups such asmethyl groups or ethyl groups, phenyl groups, amino groups, vinyl groupsand or the like are preferred.

As the shape of pores in the porous silica material for use in thepresent invention, pores one-dimensionally extending in the form of atunnel, box-shaped or ball-shaped pores three-dimensionally connectedtogether, and the like can be mentioned. Examples of the pore structureof the porous silica material for use in the present invention include,but are not limited to, two-dimensional hexagonal structures,three-dimensional hexagonal structures (P6mm, P63/mmc), cubic structures(Ia3d, Pm3n), lamellar structures, disordered structures, and the like.Examples of the porous silica material for use in the present invention,therefore, include porous silica materials of various structures.

Commercial examples of such porous silica materials include “FSM-C8”,“FSM-C10”, “FSM-C12”, “FSM-C14”, “FSM-C16”, “FSM-C18” and “FSM-C22”(all, products of Toyota Central R&D Labs. Inc.), and “MCM-41”(mesoporous molecular sieve, product of Mobil Chemical Corp.), with“FSM-C16” and “FSM-C12” being particularly preferred.

The porous silica material for use in the present invention can beproduced by condensing a skeleton raw material in the presence of asurfactant and then removing the surfactant from the condensationproduct. More specifically, it is produced by condensing a skeleton rawmaterial, such as sodium silicate, silica or an alkoxysilane, in asolution of a surfactant [production process (1)]. As an alternative, itis also produced by condensing a layer silicate (kanemite or the like)as a skeleton raw material in a solution of a surfactant [productionprocess (2)]. A description will hereinafter be made about theproduction processes (1) and (2) both of which are preferred forobtaining the porous silica material for use in the present invention.

Production Process (1)

The instant porous silica material is produced by subjecting a skeletonraw material to a condensation reaction in a solvent with a surfactantdissolved therein, collecting the resulting precipitate or the resultinggel-form solid product by filtration, washing and drying the precipitateor solid product, and then subjecting the precipitate or solid productto calcination treatment or H⁺ substitution treatment to remove thesurfactant.

Examples of the skeleton raw material include tetraalkoxysilanes andalkylalkoxysilanes containing three or four C₁₋₄ alkoxy groups,preferably tetraalkoxysilanes having four C₁₋₃ alkoxy groups, especiallypreferably tetraethoxysilane and tetramethoxysilane. These alkoxysilanescan be used either singly or in combination.

As the solvent, water or a mixed solvent of water and an organic solventmiscible with water is preferred. Examples of the organic solventinclude alcohols such as methanol, ethanol, propanol, ethylene glycoland glycerin, acetone, pyridine, acetonitrile, tetrahydrofuran, dioxane,dimethylformamide, N-methylpyrrolidone, dimethylacetamide, anddimethylsulfoxide, with methanol being particularly preferred.

No particular limitation is imposed on the surfactant. In general, acationic, anionic or nonionic surfactant can be used. Preferred examplesinclude cationic surfactants such as the chlorides, bromides, iodidesand hydroxides of alkyltrimethylammonium (C_(n)H_(2n+1)N⁺(CH₃)₃; n beingan integer of from 2 to 18), alkylammonium, dialkyldimethylammonium andbenzylammonium, with the hydroxides and bromides ofhexadecyltrimethylammonium and dodecyltrimethylammonium beingparticularly preferred.

The concentration of the surfactant may preferably be from 0.05 to 0.5mol/L, although no particular limitation is imposed thereon. Aconcentration lower than 0.05 mol/L results in incomplete formation ofpores, while a concentration higher than 0.5 mol/L leads to animpairment in the uniformity of pore diameters.

The pH control of the reaction solvent can be effected with an alkalisuch as sodium hydroxide or an acid such as hydrochloric acid subsequentto addition of a cationic surfactant. When water is used as the solvent,it is preferred to conduct the reaction at pH 10 or higher and then toneutralize the reaction mixture with an acid to pH 9 or lower (morepreferably 8 or lower). When a mixed water/alcohol solvent is used, onthe other hand, it is not specifically required to neutralize thereaction mixture with an acid subsequent to conducting the reaction atpH 10 or higher. By conducting the reaction as is without acidneutralization, the condensation can proceed.

The temperature during the reaction may preferably in a range of from−50 to 100° C. Especially when the solvent is water, a range of from 60to 80° C. is preferred. When the solvent is a mixed water/methanolsolvent, the reaction can be conducted at room temperature.

The reaction can be conducted for 1 to 48 hours or even longer, althoughthe reaction time can differ as needed depending on the reactionsolvent. When the solvent is water, for example, it is preferred toconduct the reaction for 1 hour or longer at pH 10 or higher, or for 3hours or longer at pH 9 or lower (more preferably, pH 8 or lower). Undereach of these pHs, the reaction is preferably conducted under stirring.

The instant porous silica material can be obtained by collecting,subsequent to a condensation reaction, the resulting precipitate or theresulting gel-form solid product by filtration, washing and drying theprecipitate or solid product, and then subjecting the precipitate orsolid product to calcination treatment or H⁺ substitution treatment toremove the surfactant.

According to the process relying upon conducting calcination treatment,the solid reaction product is heated at 300 to 1,000° C. (preferably 400to 700° C.). The heating time can preferably be 30 minutes or longer.For the complete removal of organic substances, it is particularlypreferred to heat the solid reaction product for 1 hour or longer. Asdescribed in the above, it is preferred to conduct the calcinationtreatment in an inert gas (nitrogen or the like) atmosphere until up toabout 400° C. to avoid burning.

According to the process relying upon conducting H⁺ substitutiontreatment with an alcohol or the like, the solid reaction product isdispersed in a solution consisting of a solvent having high solubilityfor the surfactant and a small amount of an ion source of the samecharge as the surfactant added therein. After stirring the dispersion,the resulting solid component is recovered. Examples of the solventinclude ethanol, methanol, and acetone, with ethanol being particularlypreferred.

It is to be noted that this production process can also produce a poroussilica material formed of a basic skeleton including an element (forexample, a metal element) other than silicon. Typically, the productioncan be realized by adding, as raw materials for forming the basicskeleton, sodium silicate, silica or an alkoxysilane together with acompound containing an element other than silicon and then conductingthe above-described condensation reaction.

Production Process (2)

The instant porous silica material is produced by subjecting a layermaterial such as a layer silicate as a skeleton raw material to acondensation reaction in a solvent with a surfactant dissolved therein,collecting the resulting solid product by filtration, washing and dryingthe solid product, and then subjecting the solid product to calcinationtreatment or H⁺ substitution treatment to remove the surfactant.

As the layer silicate for use as the skeleton raw material, it ispossible to use at least one or more silicates selected from the groupconsisting of kanemite (NaHSi₂O₃.3H₂O), sodium disilicate crystals (α,β,γ,δ-Na₂Si₂O₃), makatite (Na₂Si₄O₉.5H₂O), ilerite (Na₂Si₈O₁₇.XH₂O),magadiite (Na₂Si₁₄O₂₉.XH₂O), kenyaite (Na₂Si₂₀O₄₁.XH₂O) and the like.

Other usable layer silicates include, for example, those obtained bytreating clay minerals, such as sepiolite, montmorillonite, vermiculite,mica, kaolinite and smectite with an acidic aqueous solution to removeelements other than silica. It is also possible to use one or moresilicates other than layer silicates, which are selected from the groupconsisting of water glass, glass, amorphous sodium silicate, siliconalkoxides (tetraethyl orthosilicate and the like), and the like.

No particular limitation is imposed on the surfactant. In general, avariety of surfactants which are cationic, anionic or nonionic can bementioned. Preferred examples include cationic surfactants such as thechlorides, bromides, iodides and hydroxides of alkyltrimethylammonium(C_(n)H_(2n+1)N⁺(CH₃)₃; n being an integer of from 2 to 18),alkylammonium, dialkyldimethylammonium and benzylammonium. In addition,fatty acid salts, alkylsulfonate salts, alkylphosphate salts,polyethylene-oxide-based ionic surfactants, and the like are alsousable. It is to be noted that as the surfactant, these exemplifiedsurfactants can be used either singly or in combination.

The layer silicate and the surfactant are mixed together under acidic oralkaline conditions, and as a result, the layer silicate is partiallycondensed.

The concentration of the surfactant may preferably be from 0.05 to 0.5mol/L, although no particular limitation is imposed thereon. Aconcentration lower than 0.05 mol/L results in incomplete formation ofpores, while a concentration higher than 0.5 mol/L leads to animpairment in the uniformity of pore diameters.

The solvent which makes up the reaction system can preferably be water.As an alternative, a mixed solvent with a water-miscible organic solventsuch as an alcohol mixed therein is also usable.

Examples of the organic solvent include alcohols such as methanol,ethanol, propanol, ethylene glycol and glycerin, acetone, pyridine,acetonitrile, tetrahydrofuran, dioxane, dimethylformamide,N-methylpyrrolidone, dimethylacetamide, and dimethylsulfoxide, withmethanol being particularly preferred.

The condensation reaction can be conducted preferably under theconditions that the solution with the layer silicate dispersed thereinis heated at 30 to 100° C. (more preferably at 60 to 80° C., still morepreferably at 70 to 80° C.), and the reaction time can be set preferablyfor 2 to 24 hours. It is also preferred to stir the dispersion duringthe reaction under heating.

The pH of the dispersion may be controlled preferably at 10 or higherduring an initial stage (typically, the first 1 to 5 hours) of thecondensation reaction, and subsequently (typically, after an elapse for1 hour or longer), at 10 or lower.

The pH control can be effected with an alkali such as sodium hydroxideor an acid such as hydrochloric acid. By such pH control, a poroussilica material excellent in crystallinity and heat resistance can beobtained. It is to be noted that, as kanemite is alkaline, the pH of itsdispersion can generally be 10 or higher without any particularadjustment when the solvent is water.

By conducting such a dehydrating condensation reaction, a structure(porous silica precursor) is obtained with pores formed using theemployed surfactant as templates. Accordingly, subsequent to thecompletion of the condensation reaction, the resulting solid reactionproduct (porous silica precursor) is collected by filtration from thedispersion. It is preferred to repeatedly wash the thus-obtained solidreaction product with water at this stage. It is desired to dry thesolid reaction product after the washing.

By subsequently subjecting the solid reaction product to calcinationtreatment preferably at a temperature at 550° C. or higher or to H⁺substitution treatment with a hydrochloric acid/ethanol solution, thesurfactant held as the templates within the pores of the precursor canbe removed. When a cationic surfactant is used, for example, the solidreaction product is dispersed in ethanol with a small amount ofhydrochloric acid added therein, and stirring is then conducted withheating at 50 to 70° C. In the case of an anionic surfactant, thesurfactant can be extracted in a solvent with anions added therein. Inthe case of a nonionic surfactant, on the other hand, the surfactant canbe extracted with a solvent only. When the above-described calcinationtreatment is conducted, it is preferred to conduct the calcinationtreatment in an inert gas (nitrogen or the like) atmosphere to avoidburning. Even in this case, however, it is preferred, from the viewpointof preventing carbon and the like from remaining, to convert theatmosphere into an oxidizing atmosphere such as air in a final stage ofthe calcination treatment.

By the above-mentioned treatment step, the templates are removed toleave pores behind so that the desired porous silica material isproduced.

In the process for producing a porous silica material by using a layermaterial, the use of a layer material having a basic skeleton containingan element other than silicon makes it possible to produce a porousmaterial having such a basic skeleton. As a method for adding an elementother than silicon into the above-described porous material, thefollowing methods can be mentioned: (1) to incorporate the element otherthan silica in a layer silicate as a raw material, (in other words, touse a layer silicate containing the element other than silicon), and (2)to add a substance, which contains the element other than silicon, inthe course of the synthesis of the porous silica material. Toincorporate an element other than silicon (for example, aluminum) asdescribed above, aluminum nitrate, sodium aluminate or the like can beused.

The average pore diameter of the porous silica material for use in thepresent invention can be preferably from 1 to 20 nm, more preferablyfrom 1.5 to 10 nm, especially preferably from 2 to 3 nm.

The specific surface area of the porous silica material for use in thepresent invention can be preferably from 100 to 2,000 m²/g, morepreferably from 600 to 1,800 m²/g, especially preferably from 800 to1,500 m²/g. It is to be noted that the specific surface area can bemeasured by the adsorption method.

The mixing weight ratio of the porous silica material to the very slightwater-soluble drug to be used in the present invention can be preferablyfrom 0.1:1 to 1,000:1, more preferably from 0.5:1 to 100:1, especiallypreferably from 1:1 to 50:1.

Examples of carbon dioxide for use in the present invention includeliquid carbon dioxide, gaseous carbon dioxide, and dry ice.

The term “supercritical state” as used herein means a state in which thepressure and the temperature both exceed the critical points (in thecase of carbon dioxide, pressure: about 7.38 MPa, temperature: about31.0° C.), while the term “subcritical state” as used herein means astate in which only one of the pressure and the temperature exceeds thecorresponding critical point. The term “critical points” has a meaning,for example, as described in detail by J. W. Tom and P. G. Debenedettiin FIG. 1 of “Particle Formation with Superctirical Fluids—A Review”, J.Aerosol Sci., 22(5), 555-584 (1991).

The weight ratio of the extremely poorly water-soluble drug to thesupercritical fluid or subcritical fluid of carbon dioxide in thepresent invention can be preferably from 1:1 to 1:1,000,000, morepreferably from 1:10 to 1:100,000, especially preferably from 1:50 to1:50,000.

The time of the treatment with the supercritical fluid or subcriticalfluid of carbon dioxide in the present invention can be preferably from1 minute to 24 hours, more preferably from 0.5 to 12 hours, especiallypreferably from 1 to 8 hours.

The treatment with the supercritical fluid or subcritical fluid ofcarbon dioxide in the present invention can be conducted in a pressurevessel, a supercritical extraction system, a supercritical micronizationsystem, another testing system for supercritical fluid or subcriticalfluid, or the like. Illustrative are “PORTABLE REACTOR” (manufactured byTaiatsu Techno Corporation), “SUPERCRITICAL EXTRACTION SYSTEM SCF-GET”(manufactured by JASCO Corporation), and “SUPERCRITRICAL MICRONIZATIONSYSTEM SC SPRAYER” (manufactured by Nikkiso Co., Ltd.). These treatmentvessels can each have a construction equipped with a stirring mechanismto stir the supercritical fluid or subcritical fluid.

The temperature of the treatment with the supercritical fluid orsubcritical fluid in the present invention can be preferably from −40 to100° C., more preferably from 0 to 80° C., especially preferably from 10to 60° C., although it differs depending on the kind of the extremelypoorly water-soluble drug.

The pressure of the treatment with the supercritical fluid orsubcritical fluid in the present invention can be preferably from 1 to50 MPa, more preferably from 1 to 40 MPa, especially preferably from 6to 30 MPa, although it differs depending on the kind of the extremelypoorly water-soluble drug.

No particular limitation is imposed on the production step of treatingwith the supercritical fluid or subcritical fluid of carbon dioxide inthe present invention. For example, the following production processescan be mentioned: (1) placing the instant porous silica material and thevery slight water-soluble drug in a pressure vessel, filling thepressure vessel with carbon dioxide, treating the porous silica materialand the extremely poorly water-soluble drug while controlling atemperature and pressure within the vessel such that carbon dioxide ismaintained in a supercritical state or subcritical state, and thendischarging carbon dioxide to recover the resulting composition, (2)placing the instant porous silica material and the extremely poorlywater-soluble drug in a pressure vessel, controlling a temperaturewithin the vessel such that carbon dioxide will be maintained in asupercritical state or subcritical state, filling the pressure vesselwith carbon dioxide at such a pressure that carbon dioxide is maintainedin the supercritical state or subcritical state, maintaining thesupercritical state or subcritical state to treat the porous silicamaterial and the extremely poorly water-soluble drug, and thendischarging carbon dioxide to recover the resulting composition.

In general, the composition according to the present invention obtainedas described above, said composition containing the extremely poorlywater-soluble drug, can have a weight average particle size preferablyof from 1 μm or greater, more preferably of from 1 to 2,000 μm,particularly preferably of from 3 to 500 μm. It is to be noted that theweight average particle size can be measured by laser diffractometry,and the like.

Upon treating the porous silica material and the extremely poorlywater-soluble drug with the supercritical fluid or subcritical fluid ofcarbon dioxide in the present invention, various components authorizedas drug additives can be added as desired insofar as they do not impairthe advantageous effects of the present invention. Such components caninclude, for example, solvents, polymer compounds, and surfactants.

Examples of the solvents include water; aromatic hydrocarbons such asbenzene, toluene and xylene; ethers such as dimethyl ether, diethylether, dioxane, diethoxyethane, tetrahydrofuran and 1,2-dimethoxyethane;chlorinated organic solvents such as dichloromethane, chloroform, carbontetrachloride and 1,2-dichloroethane; alkylnitriles such as acetonitrileand propionitrile; nitroalkanes such as nitromethane and nitroethane;amides such as N,N-dimethylformamide and N,N-dimethylacetamide; ketonessuch as acetone; fatty acids such as acetic acid and oleic acid;alcohols such as methanol, ethanol and isopropanol; sulfoxides such asdimethylsulfoxide; and mixed solvents thereof.

Examples of the polymer compounds include pullulan, sodiumcarboxymethylcellulose, sodium alginate, xanthan gum,polyvinylpyrrolidone, carboxyvinyl polymer, methylcellulose,hydroxypropylmethylcellulose, carageenan, agar, and gelatin.

Examples of the surfactants include nonionic surfactants, for example,polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenatedcastor oil, polyoxyethylene alkyl ethers such as polyoxyethylene laurylether, and sorbitan fatty acid esters such as polyoxyethylene sorbitanfatty acid ester (polysolvate) and sorbitan monostearate; cationicsurfactants such as benzalconium chloride, benzethonium chloride andcetylpyridinium chloride; and anionic surfactants such as calciumstearate, magnesium stearate and sodium laurylsulfate. Also included arefluorine-containing surfactants such as ammonium carboxylateperfluoroether.

One or more of additives commonly employed in medicinal preparations canbe added to the composition according to the present invention, whichcontains the extremely poorly water-soluble drug, to produce an oralpreparation or parenteral preparation, although as a medicinalpreparation, the composition can be used as is.

Exemplified as additives for oral preparations are excipients such aslactose, crystalline cellulose, sucrose, mannitol, light silicicanhydride, and calcium hydrogenphosphate; binders such asmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,gelatin, polyvinylpyrrolidone, and pullulan; disintegrators such ascrosslinked sodium carboxymethylcellulose, sodiumcarboxymethylcellulose, crosslinked polyvinylpyrrolidone, andlow-substituted hydroxypropylcellulose; lubricants such as magnesiumstearate and talc; colorants such as tar colors and iron sesquioxide;and corrigents such as stevia, aspartame, and flavors.

Exemplified as additives for parenteral preparations are solvents, forexample, monohydric alcohol such as benzyl alcohol, polyhydric alcoholssuch as concentrated glycerin and 1,3-butylene glycol, esters such asdiisopropyl adipate and triacetine, ketones such as crotamiton, and oilsand fats such as oleic acid and castor oil; water-soluble polymersubstances, for example, celluloses such as hydroxyethyl cellulose andhydroxypropylcellulose, polysaccharides such as sucrose andβ-cyclodextrin; sugar alcohols such as sorbitol and mannitol, andsynthetic polymer substances such as polyvinyl alcohol,polyvinylpyrrolidone and polyacrylic acid; surfactants, for example,anionic surfactants such as calcium stearate, magnesium stearate andsodium laurylsulfate, cationic surfactants such as benzalconiumchloride, benzethonium chloride and cetylpyridium chloride, and nonionicsurfactants such as glycerin monostearate, sugar fatty acid esters,polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitanfatty acid esters; enhancers, for example, esters such asisopropylmyristate, terpenes such as L-menthol and dL-camphor, andhigher fatty acids such as oleic acid; stabilizers, for example,phenolic substances such as methyl paraoxybenzoate and propylparaoxybenzoate, neutral substances such as chlorobutanol andphenylethyl alcohol, cationic soaps such as benzalconium chloride andbenzethonium chloride, antioxidants such as vitamin E andbuthylhydroxyanisole, reducing agents such as ascorbic acid, sodiumhydrogensulfite and sodium thiosulfate, and chelating agents such ascitric acid and tartaric acid and salts thereof, lecithin,ethylenediamine tetraacetate (edetic acid); pH adjustors such asphosphoric acid, acetic acid, boric acid, succinic acid, phthalic acidand salts thereof, glycine, and sodium hydroxide; and bases such aspolyacrylic acid (sodium salt), polyvinylpyrrolidone, polyvinyl alcohol,carboxyvinyl polymer, gelatin, and starch.

Exemplified as the forms of preparations according to the presentinvention are oral preparations such as tablets, capsules, granules andsubtilized granules; and parenteral preparations such as injections,suppositories, vaginal preparations, sublingual preparations, implants,instillations and sprays.

EXAMPLES

The present invention will be described more specifically on the basisof examples and comparative examples, although the present inventionshall not be limited to or by the following examples.

Example 1

Compound A (30 mg), “FSM-C16” (product of Toyota Central R&D Labs. Inc.;300 mg) and dry ice (120 g) were placed in a “PORTABLE REACTOR”(manufactured by Taiatsu Techno Corporation), and were heated to 50° C.to raise the pressure to 18 MPa. At those temperature and pressure, thecontents were maintained under stirring for 5 hours. Subsequently, theheating was stopped, and the reaction mixture was allowed to stand untilits temperature dropped to room temperature. After carbon dioxide wasdischarged, a composition with the extremely poorly water-soluble drugcontained therein was obtained.

Example 2

Compound A (30 mg), “FSM-C12” (product of Toyota Central R&D Labs. Inc.;300 mg) and dry ice (120 g) were placed in a “PORTABLE REACTOR”, andwere heated to 50° C. to raise the pressure to 18 MPa. At thosetemperature and pressure, the contents were maintained under stirringfor 5 hours. Subsequently, the heating was stopped, and the reactionmixture was allowed to stand until its temperature dropped to roomtemperature. After carbon dioxide was discharged, a composition with theextremely poorly water-soluble drug contained therein was obtained.

Comparative Example 1

Compound A (30 mg) and “FSM-C16” (300 mg) were mixed in a mortar toobtain a composition with the extremely poorly water-soluble drugcontained therein.

Comparative Example 2

Compound A (30 mg) and dry ice (120 g) were placed in a “PORTABLEREACTOR”, and were heated to 50° C. to raise the pressure to 18 MPa. Atthose temperature and pressure, the contents were maintained understirring for 5 hours. Subsequently, the heating was stopped, and thereaction mixture was allowed to stand until its temperature dropped toroom temperature. After carbon dioxide was discharged, a compositionwith the extremely poorly water-soluble drug contained therein wasobtained.

Dissolution Test

With respect to the compositions containing the extremely poorlywater-soluble drug and obtained in Examples 1-2 and Comparative Examples1-2, a dissolution test was conducted. The dissolution test wasconducted in accordance with The Pharmacopoeia of Japan, General Tests,Dissolution Test, Method 2 (paddle method). Each composition with theextremely poorly water-soluble drug (Compound A, 5 mg) contained thereinwas added to a test solution (0.3% aqueous solution of sodiumlaurylsulfate; 900 mL), and a dissolution test was conducted under thefollowing conditions: temperature: 37±1° C., paddle rotation speed: 50rpm).

After 5, 30, 60 and 120 minutes, Compound A dissolved in the testsolution was quantified by liquid chromatography while using a reversedphase column (“INERTSILODS-2”, product of GL Sciences Inc.), anddissolution rates (%) were calculated.

The results of the measurement are shown in Table 1.

TABLE 1 Comparative Example Example 1 2 1 2 Compound A (mg) 30 30 30 30“FSM-C16” (mg) 300 — 300 — “FSM-C12” (mg) — 300 — — Dry ice (g) 120 120— 120 Average pore diameter (nm) 3 2 3 — Dissolution Stirring time (min)rate (%) 5 29.5 22.0 3.9 0.0 30 54.8 40.7 7.6 1.7 60 63.9 51.2 10.0 1.1120 74.7 57.2 14.3 2.2

From the composition containing the extremely poorly water soluble drugobtained by simply physically mixing Compound A and the porous silicamaterial (Comparative Example 1) and the composition containing theextremely poorly water soluble drug obtained by conducting treatment ofCompound A with supercritical carbon dioxide without inclusion of theporous silica material (Comparative Example 2), Compound A was notdissolved practically. On the other hand, the compositions containingthe extremely poorly water soluble drug according to the presentinvention, which were obtained by adding Compound A and the poroussilica material and treating them with supercritical carbon dioxide(Examples 1-2), both exhibited dramatic improvements in the dissolutionof Compound A.

Production Example 1

The composition (150 g) of Example 1, which contained the extremelypoorly water-soluble drug, was classified by a “NEW SPEED MILL ND-02”(manufactured by Okada Seiko Co., Ltd.) equipped with a screen having anopening size of 1 mm in diameter. The thus-classified composition withthe extremely poorly water-soluble drug contained therein (110 g),lactose (100 mesh lactose, product of DMV NV, 42 g), crystallinecellulose (“AVICEL PH-102”, product of Asahi Kasei Corporation, 100 g)and low-substituted hydroxypropylcellulose [“L-HPC(LH-11)”, product ofShin-Etsu Chemical Co., Ltd., 45 g] were mixed for 10 minutes by aV-blender. Magnesium stearate (3 g) was added to the mixture, followedby further mixing for 5 minutes in the twin-cylinder mixer. Theresulting mixture was compressed into tables on a tablet machine(“AP-38”, manufactured by Hata Iron Works Co., Ltd.) to produce tablesof 300 mg/table (each contained 100 mg of Compound A).

1. A composition, comprising: an extremely poorly water-soluble drug;and a porous silica material; wherein: the composition is obtained bytreating a mixture comprising the porous silica material and theextremely poorly water-soluble drug with a supercritical fluid orsubcritical fluid of carbon dioxide; the extremely poorly water-solubledrug has a solubility in water at 25° C. of less than 10 μg/mL prior totreatment; the porous silica material has an average pore diameter offrom 1 to 20 nm, a total pore volume of pores having diameters within±40% of the average pore diameter accounts for at least 60% of a volumeof all pores of the porous silica material, and the porous silicamaterial has an X-ray diffraction pattern including at least one peak ata position of a diffraction angle (2θ) corresponding to a d value of atleast 1 nm; and the composition is suitable for oral administration. 2.The composition according to claim 1, wherein the porous silica materialhas a specific surface area of from 100 to 2,000 m²/g.
 3. Thecomposition according to claim 1, wherein a mixing ratio the poroussilica material to the extremely poorly water-soluble drug is from 0.1:1to 1,000:1.
 4. The composition according to claim 1, wherein theextremely poorly water-soluble drug comprises2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one.5. A medicinal preparation comprising: the composition according toclaim 1; and an additive.
 6. A process for producing the compositionaccording to claim 1, comprising: placing a porous silica material andan extremely poorly water-soluble drug in a pressure-resistant vessel;filling the pressure-resistant vessel with carbon dioxide; maintainingthe vessel at a temperature and pressure such that the carbon dioxide ismaintained as a supercritical fluid or a subcritical fluid; anddischarging the carbon dioxide to recover the resulting composition;wherein the porous silica material has an average pore diameter of from1 to 20 nm, a total pore volume of pores having diameters within ±40% ofthe average pore diameter accounts for at least 60% of a volume of allpores of the porous silica material, and the porous silica material hasan X-ray diffraction pattern including at least one peak at a positionof a diffraction angle (2θ) corresponding to a d value of at least 1 nm.7. The process of claim 6, wherein a weight ratio of the extremelypoorly water-soluble drug to the supercritical fluid or subcriticalfluid of carbon dioxide is from 1:1 to 1:1,000,000.
 8. The process ofclaim 6, wherein maintaining the vessel comprises maintaining the vesselat a temperature of from −40 to 100° C.
 9. The process of claim 6,wherein maintaining the vessel comprises maintaining the vessel at apressure of from 1 to 50 MPa.
 10. The process of claim 6, wherein theporous silica material and the extremely poorly water-soluble drug aremaintained in contact with the supercritical fluid or subcritical fluidof carbon dioxide for a period of from 1 minute to 24 hours.
 11. Aprocess for producing a composition according to claim 1, comprising:placing a porous silica material and an extremely poorly water-solubledrug in a pressure-resistant vessel; maintaining the vessel at atemperature at which carbon dioxide is in the form of a supercriticalfluid or a subcritical fluid; filling the vessel with carbon dioxide ata pressure such that carbon dioxide is in the form of a supercriticalfluid or a subcritical fluid; treating the porous silica material andthe extremely poorly water-soluble drug with the supercritical fluid orsubcritical fluid of carbon dioxide; and discharging carbon dioxide torecover the resulting composition; wherein the porous silica materialhas an average pore diameter of from 1 to 20 nm, a total pore volume ofpores having diameters within ±40% of the average pore diameter accountsfor at least 60% of a volume of all pores of the porous silica material,and the porous silica material has an X-ray diffraction patternincluding at least one peak at a position of a diffraction angle (2θ)corresponding to a d value of at least 1 nm.
 12. The process accordingto claim 11, wherein a weight ratio of the extremely poorlywater-soluble drug to the supercritical fluid or subcritical fluid ofcarbon dioxide is from 1:1 to 1:1,000,000.
 13. The process according toclaim 11, wherein treating the porous silica material and the extremelypoorly water-soluble drug comprises treating at a temperature of from−40 to 100° C.
 14. The process according to claim 11, wherein treatingthe porous silica material and the extremely poorly water-soluble drugcomprises treating at a pressure of from 1 to 50 MPa.
 15. The processaccording to claim 11, wherein treating the porous silica material andthe extremely poorly water-soluble drug comprises treating for a periodof from 1 minute to 24 hours.